Central nervous system/neurological disorders affect a wide range of the population with differing severity. CNS/neurological disorders can include, but are not limited to anxiety, depression, pain, sleep disorders and substance abuse/dependence. There remains a great need to effective treatment of these and various other CNS/neurological disorders.
The ORL-1 (orphan opioid receptor, now also known as NOP) G-protein coupled receptor, also known as the nociceptin receptor, was first reported in 1994, and was discovered based on its homology with the classic δ-, μ-, and κ-opioid receptors. The endogenous ligand of ORL-1 (NOP), known as nociceptin, a highly basic 17 amino acid peptide, was isolated from tissue extracts in 1995. Nociceptin plays an important role in the function of central nervous system such as learning, memory, anxiety and stress (Br. J. Pharmacol. 129, 1261-1283 (2000)).
The ORL-1 receptor is widely distributed/expressed throughout the human body, including in the brain and spinal cord. In the spinal cord, the ORL-1 receptor exists in both the dorsal and ventral horns, and precursor mRNA has been found in the superficial lamina of the dorsal horn, where primary afferent fibers of nociceptors terminate. Therefore, the ORL-1 has an important role in nociception transmission in the spinal cord.
Nociceptin binding to ORL-1 receptors causes inhibition of cAMP synthesis, inhibition of voltage-gated calcium channels, and activation of potassium conductance. In vivo, nociceptin produces a variety of pharmacological effects that at times oppose those of the opioids, including hyperalgesia and inhibition of morphine-induced analgesia.
The Nociceptin receptor (NOPr) is a target for the treatment of pain and substance abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociceptin, but also potentially blocks the rewarding effects of several abused drugs, such as morphine, cocaine and amphetamine.
Substance abuse and dependence involves any of following classes of substances: alcohol, amphetamine, methamphetamine, cannabis (including marijuana, hashish), cocaine, hallucinogens (including LSD, mescaline, MDMA), nicotine, opioids (including morphine, heroin, codeine, methadone), phencyclidine, ketamine, barbiturates, benzodiazepines (including diazepam, triazolam), inhalants (including toluene, paint thinner).
It is known that nociceptin is effective in alcohol dependence (Ciccocioppo et al., Psychopharmacology (Berl). 141, 220-224, 1999; Ciccocioppo et al., Psychopharmacology (Berl) 172, 170-178, 2004; Martin-Fardon et al., NeuroReport. 11, 1939-1943, 2000), morphine or cocaine dependence (Sakoori et al., Psychopharmacology (Berl) 172, 129-136, 2004), methamphetamine dependence (Zhao et al., NeuroReport. 14, 2383-2385, 2003).
Therefore a small molecule ORL-1 receptor (NOP) agonist is expected to be effective in the prophylaxis or treatment of for substance abuse and dependence. However, first synthesized ORL-1 receptor agonist Ro64-6198 failed to decrease alcohol drinking, rather increase it at high dose (Economidou et al., Peptides 27, 3299-3306, 2006). This effect probably induced by its residual agonistic activity at μ-opioid receptors.
In view of the above, there remains a need for effective treatments of various neurological disorders, including but not limited to, anxiety, depression, pain, sleep disorders and substance abuse/dependence.